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- EMDB-75616: Structure of human TRPV1 in Apo state -

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Basic information

Entry
Database: EMDB / ID: EMD-75616
TitleStructure of human TRPV1 in Apo state
Map data
Sample
  • Complex: Tetrameric hTRPV1 in the apo state
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 1
  • Ligand: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctadecanoate
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
KeywordsMembrane Protein / Ion Channel / TRPV1 / Mavatrep / Asivatrep / JNJ-17203212 / CAY10448 / Small Molecule / Pain / Thermosensing / GDN / Antagonist
Function / homology
Function and homology information


chemosensory behavior / response to capsazepine / sensory perception of mechanical stimulus / peptide secretion / temperature-gated ion channel activity / detection of chemical stimulus involved in sensory perception of pain / smooth muscle contraction involved in micturition / fever generation / detection of temperature stimulus involved in thermoception / thermoception ...chemosensory behavior / response to capsazepine / sensory perception of mechanical stimulus / peptide secretion / temperature-gated ion channel activity / detection of chemical stimulus involved in sensory perception of pain / smooth muscle contraction involved in micturition / fever generation / detection of temperature stimulus involved in thermoception / thermoception / excitatory extracellular ligand-gated monoatomic ion channel activity / dendritic spine membrane / diet induced thermogenesis / TRP channels / cellular response to alkaloid / cellular response to ATP / intracellularly gated calcium channel activity / detection of temperature stimulus involved in sensory perception of pain / calcium ion import across plasma membrane / behavioral response to pain / voltage-gated calcium channel activity / cellular response to acidic pH / extracellular ligand-gated monoatomic ion channel activity / phosphatidylinositol binding / lipid metabolic process / phosphoprotein binding / GABA-ergic synapse / calcium ion transmembrane transport / calcium channel activity / transmembrane signaling receptor activity / cellular response to heat / sensory perception of taste / protein homotetramerization / calmodulin binding / postsynaptic membrane / cell surface receptor signaling pathway / negative regulation of transcription by RNA polymerase II / ATP binding / membrane / metal ion binding / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Ankyrin repeat profile. / Ankyrin repeats (3 copies) / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily V member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.52 Å
AuthorsLopez KE / Van Horn WD
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS119505 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM141933 United States
American Heart Association23POST1029540 United States
CitationJournal: bioRxiv / Year: 2026
Title: TRPV1 antagonism occurs through diverse structural mechanisms.
Authors: Kyle E Lopez / Audrey S Paduda / Matthew J Derrick / Wade D Van Horn /
Abstract: Transient receptor potential vanilloid 1 (TRPV1) ion channel mediates thermosensation and pain and is a target for non-addictive analgesics; however, clinical candidates have failed due to ...Transient receptor potential vanilloid 1 (TRPV1) ion channel mediates thermosensation and pain and is a target for non-addictive analgesics; however, clinical candidates have failed due to thermoregulatory side effects. Limited structural data for human TRPV1 (hTRPV1) bound to clinically relevant antagonists has constrained mechanistic insight. Using chemoinformatics-informed cryo-EM and BRET assays, we define the structural basis of antagonism across diverse chemotypes, including failed clinical compounds. A structure of hTRPV1 bound to 6-iodo-dihydrocapsaicin shows how a single substitution converts an agonist into an antagonist. Additional structures with Asivatrep, Mavatrep, and JNJ-17203212 reveal vanilloid pocket plasticity and divergent interaction networks, including lipid co-binding. Despite this diversity, antagonists converge on a conserved inhibited state, showing high potency is maintained across flexible binding modes. These findings redefine our understanding of hTRPV1 antagonism and illustrate how chemically diverse ligands stabilize an inhibited state in polymodal ion channels, laying groundwork for next-generation analgesics with improved safety.
History
DepositionFeb 17, 2026-
Header (metadata) releaseJun 3, 2026-
Map releaseJun 3, 2026-
UpdateJun 3, 2026-
Current statusJun 3, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75616.png

Downloads & links

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Map

FileDownload / File: emd_75616.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 480 pix.
= 350.208 Å		0.73 Å/pix.
x 480 pix.
= 350.208 Å		0.73 Å/pix.
x 480 pix.
= 350.208 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.7296 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy EMDB: 0.2
Minimum - Maximum-1.1203377 - 1.777318
Average (Standard dev.)0.0004611197 (±0.028598635)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 350.208 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_75616_msk_1.map
Projections & Slices
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Histogram

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Half map: #1

Fileemd_75616_half_map_1.map
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Half map: #2

Fileemd_75616_half_map_2.map
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Sample components

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Entire : Tetrameric hTRPV1 in the apo state

EntireName: Tetrameric hTRPV1 in the apo state
Components
  • Complex: Tetrameric hTRPV1 in the apo state
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 1
  • Ligand: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctadecanoate
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate

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Supramolecule #1: Tetrameric hTRPV1 in the apo state

SupramoleculeName: Tetrameric hTRPV1 in the apo state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 496.528 KDa

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Macromolecule #1: Transient receptor potential cation channel subfamily V member 1

MacromoleculeName: Transient receptor potential cation channel subfamily V member 1
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 124.281469 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKKWSSTDLG AAADPLQKDT CPDPLDGDPN SRPPPAKPQL STAKSRTRLF GKGDSEEAFP VDCPHEEGEL DSCPTITVSP VITIQRPGD GPTGARLLSQ DSVAASTEKT LRLYDRRSIF EAVAQNNCQD LESLLLFLQK SKKHLTDNEF KDPETGKTCL L KAMLNLHD ...String:
MKKWSSTDLG AAADPLQKDT CPDPLDGDPN SRPPPAKPQL STAKSRTRLF GKGDSEEAFP VDCPHEEGEL DSCPTITVSP VITIQRPGD GPTGARLLSQ DSVAASTEKT LRLYDRRSIF EAVAQNNCQD LESLLLFLQK SKKHLTDNEF KDPETGKTCL L KAMLNLHD GQNTTIPLLL EIARQTDSLK ELVNASYTDS YYKGQTALHI AIERRNMALV TLLVENGADV QAAAHGDFFK KT KGRPGFY FGELPLSLAA CTNQLGIVKF LLQNSWQTAD ISARDSVGNT VLHALVEVAD NTADNTKFVT SMYNEILILG AKL HPTLKL EELTNKKGMT PLALAAGTGK IGVLAYILQR EIQEPECRHL SRKFTEWAYG PVHSSLYDLS CIDTCEKNSV LEVI AYSSS ETPNRHDMLL VEPLNRLLQD KWDRFVKRIF YFNFLVYCLY MIIFTMAAYY RPVDGLPPFK MEKTGDYFRV TGEIL SVLG GVYFFFRGIQ YFLQRRPSMK TLFVDSYSEM LFFLQSLFML ATVVLYFSHL KEYVASMVFS LALGWTNMLY YTRGFQ QMG IYAVMIEKMI LRDLCRFMFV YIVFLFGFST AVVTLIEDGK NDSLPSESTS HRWRGPACRP PDSSYNSLYS TCLELFK FT IGMGDLEFTE NYDFKAVFII LLLAYVILTY ILLLNMLIAL MGETVNKIAQ ESKNIWKLQR AITILDTEKS FLKCMRKA F RSGKLLQVGY TPDGKDDYRW CFRVDEVNWT TWNTNVGIIN EDPGNCEGVK RTLSFSLRSS RVSGRHWKNF ALVPLLREA SARDRQSAQP EEVYLRQFSG SLKPEDAEVF KSPAASGEKG TLEVLFQGPG GSGGSASVIK PEMKIKLRME GAVNGHKFVI EGEGIGKPY EGTQTLDLTV EEGAPLPFSY DILTPAFQYG NRAFTKYPED IPDYFKQAFP EGYSWERSMT YEDQGICIAT S DITMEGDC FFYEIRFDGT NFPPNGPVMQ KKTLKWEPST EKMYVEDGVL KGDVEMALLL EGGGHYRCDF KTTYKAKKDV RL PDAHEVD HRIEILSHDK DYNKVRLYEH AEARYSGGGS GGGHHHHHHH GGSGGWSHPQ FEK

UniProtKB: Transient receptor potential cation channel subfamily V member 1

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Macromolecule #2: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxyc...

MacromoleculeName: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctadecanoate
type: ligand / ID: 2 / Number of copies: 4 / Formula: 8IJ
Molecular weightTheoretical: 867.138 Da
Chemical component information

ChemComp-8IJ:
(2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctadecanoate

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Macromolecule #3: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 3 / Number of copies: 4 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.75 mg/mL
BufferpH: 8
Component:
ConcentrationName
20.0 mMTris-HCl
150.0 mMSodium Chloride
1.0 mM2-Mercaptoethanol
0.01 %Glyco-diosgeenin
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Number real images: 15756 / Average exposure time: 4.1 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1646090
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.52 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 153457
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 4 / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8gfa


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: RIGID BODY FIT
Output model

PDB-11cj:
Structure of human TRPV1 in Apo state

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